USPTO Patents Application 09993647

REMARKS

The Claimed Invention

Claims 74,81,87,93, 100-104, 106-109, 111-115 and 117-119 are pending in
this application.

Claims 74, 81, 87, 93, 100-104, 106-109, 111-115, 118 and 119 define
methods of treatment using A^-(4-chloro-3-(trifluoromethyl) phenyl)-A^'-(4-(2-(A^-
methylcarbamoyl)-4-pyridyloxy) phenyl) urea (Sorafenib), the tosylate salt form for
which the drug Nexavar®, and A^-(4-chloro-3-(trifluoromethyl) phenyl) -AT- (4- (2-
(carbamoyl)-4-pyridyloxy) phenyl) urea, a derivative of Sorafenib.

As indicated in the previous response, Claim 117 defines a method for
inhibiting raf-kinase in a human or mammal by administering one of these two
compounds to a human or other mammal in need thereof. It does not require the
treatment of a disease such as cancer in a human or other mammal. It only requires
that the inhibition of raf kinase within the human or other mammal be inhibited.
Such activity is clearly enabled by the assays in the disclosure.

Claims to treating carcinoma of the colon

Applicants acknowledge that claims 104, 115, 118 and 119 directed to treating
carcinoma of the colon have been found to satisfy 35 USC § 1 12, first paragraph.
Given the scope of the disclosure provided, including the enabling disclosure for
treating carcinoma of the colon, it would at most involve routine experimentation, if
any at all, for one of ordinary skill in the art to treat other solid tumors with one of the
two compounds named. Explicitly providing dedicated assays for each form of
cancer is not necessary to enable the methods claimed. See, for example, In re
Howarth, 654 F.2d 105, 210 U.S.P.Q. 689 (CCPA 1981) ("An inventor need not ...
explain every detail since he is speaking to those skilled in the art.)

Rejection under 35 U.S.C. §112, first paragraph

Claims 74, 81, 87, 93, 100-103, 106-108, 110-114 and 117 stand rejected
under 35 U.S.C. §112, first paragraph.

The examiner has yet to provide any direct evidence that one skilled in the art
would not find the claimed subject matter enabled by the specification. Since the last
response, the drug Nexavar has been approved in more countries and has been
enrolled in more clinical trials. The number of clinical trails reported on
www.clinicaltrials.gov employing Nexavar is now 326. As indicated in the last
response, Nexavar® has been studied in more than 20 tumor types and in nearly 8000
clinical trial patients. yww.msdicainewstociay.corr)/artlcles/42734.php, including lung,
thyroid, gastric and ovarian cancers, as shown by the publications made of record
earlier and discussed below. In the previous response Applicants cited specific
studies on multiple cancers by Awada et al., Br J Cancer. 2005 May 23;92(10):1855-
61, Clark et al, Clinical Cancer Res.2005 Aug 1,1 1(15):5472-80, Moore et al, Ann
Oncol. 2005 Oct; 16 (10):1688-94.Epub 2005 Jul 8, Escudier et al, N Engl J Med
2007 Jan 11, 356 (2): 125-34.

This 320 clinical studies including those of Awada et al, Clark et al, Moore et
al., and Escudier et al, 1) demonstrate it does not require undue experimentation to
practice the claimed methods from applicants disclosure and 2) demonstrate there is
correlation between the models disclosed in the application and efficacy in contrast to
the studies by Johnson et al. cited by the examiner.

The approved use of Nexavar and the methods employed in the studies above
are consistent with the teachings of the disclosure of this invention. No evidence has
been presented that any researcher needed to significantly deviate from the teachings
within this application to use Nexavar or that the assays disclosed were ineffective in
identifying active compounds.

These clinical studies endorse the teachings in the specification and
demonstrate the claimed methods are enabled by the specification. The dosages,
modes of administration and patient classes used in these studies are consistent with
the teachings in this specification. No evidence has been presented to question the
teachings within the specification to support the rejection.

Applicants rely on the state of the art references (Monia, Kolch, Daum et al.
and Fridman et al) to show the correlation between the inhibition of raf kinase with
the inhibition of the growth of a variety of solid tumor types (Monia et al.), the
blocking cell proliferation (Kolch et al.) and the reversion of transformed cells to the
normal growth phenotype (Daum et al., Fridman et al).

Applicants do not rely on Awada et al, Clark et al, Moore et al., and Escudier
et al, to show the state of the art and need not do so since the disclosure is clearly
enabling for the methods claimed. Applicants need not provide any references to
show the claimed uses were conventional.

The disclosure in the specification provides the details necessary to establish
therapeutic treatments with the compounds disclosed therein. The adequacy of this
disclosure is confirmed by the studies discusses above and others made of record in
the IDS filed on June 29 2007.

The Examiner maintains "There is no evidence of record that the claimed
compounds are actually efficacious in treating all types of solid tumor, carcinoma,
myeloid disorders or adenoma or inhibit RAF-kinase generally." This is clearly not
true in view of the numerous studies made of record. The drug Nexavar has been
administered in thousands of patients and efficacy has been confirmed in that Nexavar
has been approved for the treatment of renal cell carcinoma (RCC) in more than 70
countries and hepatocellular carcinoma (HCC) in more than 40 countries. Nexavar
was the first drug approved for use in treating renal cell carcinoma (RCC), such that
the drugs efficacious properties are not only real, they are unique. As mentioned
above, it is reported that over 320 clinical trials are using Nexavar.

Clinical trials such as these were not performed at the time of filing but such
evidence of efficacy is not necessary to satisfy the requirements of the statute. An
applicant is not required to perform the claimed methods in clinical trials to satisfy the
statute. With regard to the requirement of utility, the Federal Circuit in In re Brana,
51 F.3d 1560, 34 USPQ 1436 (Fed. Cir. 1995), stated that:

usefulness in patent law, and in particular in the context of
pharmaceutical inventions, necessarily includes the expectation of
further research and development. The stage at which an invention
in this field becomes useful can be well before it is ready to be
administered to humans. If the courts were to require Phase II
testing in order to prove utility for pharmaceutical inventions, the
associated costs would prevent many companies from obtaining
patent protection on promising new inventions, thereby eliminating
an incentive to pursue, through research and development, potential
cures in many crucial areas.

If such testing is not required to show utility it also should not be required to
show enablement based on the same principles.

There is no requirement that an applicant provide any working examples. See,
for example, Marzocchi, supra, stating that how "an enabling teaching is set forth,
either by use of illustrative examples or by broad terminology, is of no importance ."
The MPEP also agrees by stating that "compliance with the enablement requirement
of 35 U.S.C. 112, first paragraph, does not turn on whether an example is disclosed ."
See MPEP § 2164.02.

There is clearly no requirement that Applicants provide working examples
relating to the treatment of every claimed disease to satisfy the statute. See, for
example, In re Angstadt, 537 F.2d at 502-03, 190 USPQ 214 (CCPA 1976) (deciding
that applicants "are not required to disclose every species encompassed by their
claims even in an unpredictable art"); Utter v Higara, 845 F.2d at 998-99, 6 USPQ2d
1714 (Fed. Cir. 1988) (holding that a specification may, within the meaning of
Section 112, Para. 1, enable a broadly claimed invention without describing all
species that claim encompasses).

The PTO has failed to meet its burden of establishing that the disclosure does
not enable one skilled in the art to perform the methods claimed. Instead of relying on
probative evidence, the rejection is improperly based on bare allegations and
conclusions. No evidence has been presented which would demonstrate that the
guidance provided by the specification is inadequate to enable the use of the claimed
compounds without undue experimentation.

Applicants maintain that the express disclosure within the specification is
sufficient to enable all of the claims herein and that further assays or data to support
the methods of treatment are not necessary. Based on the teachings within the art of
the broad spectrum of activity of raf kinase inhibitors, one skilled in the art would
recognize that the compounds recited in the claims herein having raf kinase activity
would be effective in treating the diseases claimed.

Claims 87, 93, 100-103,108, 109 and 111-114

The specification expressly teaches the compounds disclosed are suitable for
the treatment of the cancers named in claims 87, 93, 100-103,108, 109 and 111-
1 14,(lung, pancreas, thyroid, bladder and myeloid leukemia). There is no reason to
doubt the general and specific disclosures therein regarding the treatment of solid
tumors such as these. In addition, studies of record have confirmed the compound

Nexavar is efficacious in treating colon cancer (Awada et al, Clark et al, Moore et al ),
lung cancer (Awada et al. ), pancreatic cancer (Clark et al and Moore et al.) and
myeloid leukemia (Eclair, et al., "96 Annual Meeting, Anaheim/Orange County,
CA, April 16-20, 2005).

In the view of the lack of evidence to support the allegation that these claims
are not enabled, the methods of Claims 87, 93, 100-103,108, 109 and 111-114 are
clearly enabled by the specification and the rejection of these claims under 35 USC
§1 12 first paragraph, should be withdrawn.

Claim 117

Claim 1 17 is directed to a method of inhibiting raf -kinase in a human or other
mammal with one of the two compounds listed. No reasons have been given for
rejecting this claim as not enabled. It is not a method of treatment claim for any
condition, including cancer, so the issues raised by the examiner regarding the
complexities in treating cancer are moot.

The specification provides sufficient guidance to prepare the two urea
compounds and also provides sufficient guidance on how to prepare and administer
compositions with these compounds, including dosages. The specification also shows
that the free base of these compounds, compounds 42 and 43, inhibit raf kinase in the
assays disclosed.

The examiner has not identified any element of the claim for which the
disclosure is allegedly deficient and has not identified any claim term, which is
allegedly indefinite. Instead, the examiner reads limitations into the claim regarding
the treatment of diseases. There is no basis for incorporating treatment limitations into
the claim, which is improper, (See Phillips v. AWH Corp., 415 F.3d 1303, 1313, 75
USPQ2d 1321, 1326 (Fed. Cir. 2005) (en banc), MPEP 2111.01, and In re Zletz, 893
F.2d 319, 321, 13 USPQ2d 1320, 1322 (Fed. Cir. 1989)).

In that there is no basis for referring to the specification for the meaning of
any claim term and there clearly is no basis for reading treatment limitations into the
claim, the rejection of claim 117 should be withdrawn.

For the reasons indicated above, Applicants maintain that they have provided
more than adequate guidance and examples to enable the claimed invention and

submit all claims meet the requirements of 35 U.S.C. § 1 12, first and second
paragraphs.

The Commissioner is hereby authorized to charge any fees associated with this
response or credit any overpayment to Deposit Account No. 13-3402.

Respectfully submitted,

/Richard J. Traverso/

Richard J. Traverso, Reg. No. 30,595
Attorney for Applicant(s)

MILLEN, WHITE, ZELANO

& BRANIGAN, P.C.
Arlington Courthouse Plaza 1, Suite 1400
2200 Clarendon Boulevard
Arlington, Virginia 2220 1
Telephone: (703) 812 5310
Attorney Docket No.: BAYER-0018-A
Filed June 18, 2009